Primary Progressive Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis
Conditions
Brief summary
The study seeks to investigate safety and efficacy of ixazomib (NINLARO), a proteasome inhibitor, in multiple sclerosis (MS). Participants will receive either ixazomib capsules or placebo capsules for up to 24 months.
Detailed description
The production of antibodies in the form of oligoclonal bands (OCBs) from plasma cells (cells involved in the body's immune response), is the hallmark of MS. Recent evidence suggests that plasma cells are resident in the meninges (protective membranes of the brain and spinal cord) of people with Multiple Sclerosis (pwMS). Ixazomib is a drug which has been effective in treating multiple myeloma, a disease caused by aberrant plasma cells. The purpose of this study is to investigate whether ixazomib can reduce or clear OCBs from the cerebrospinal fluid (CSF) of pwMS. Participants will be randomly assigned to receive either ixazomib capsules (active drug arm) or placebo capsules (placebo arm) for up to 24 months. Participants with relapsing remitting MS (who are stable on disease modifying therapy) and those with progressive MS (who are not on disease modifying therapy) will be invited to take part in the study.
Interventions
DRUGIxazomib (NINLARO®) capsules / Matching placebo capsules
Participants will be treated for a maximum of 24 months
Sponsors
Queen Mary University of London
Takeda Pharmaceuticals International, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a double-blind, randomised, placebo-controlled trial. Randomisation will be stratified by disease stage, i.e. RRMS (and established on DMT) versus progressive MS (and not on DMT). The expected study duration is 36 months (a 12-month recruitment period and a 24-month treatment period). There will be 72 participants: 48 on ixazomib; 24 on placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
\- Each participant must meet all of the following inclusion criteria to be enrolled in the study: 1. Male and female patients 18 to 65 years old at screening 2. Must have a diagnosis of MS, and: * Patients with RRMS must be on DMT * Patients with progressive MS must not be on DMT 3. Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit). Patients on tecfidera, cladribine, ocrelizumab, alemtuzumab, fingolimod or natalizumab must be enrolled with caution, at Chief Investigator's (CI) discretion because of the lymphopenia caused by these drugs and the risk of thrombocytopenia in 1-2 % of people after alemtuzumab 4. OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis 5. Able and willing to give written informed consent and comply with protocol requirements with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 6. Agree to the use of effective contraception as follows: Female patients must: * Be postmenopausal for at least 1 year before the screening visit (postmenopausal status confirmed by serum Follicle Stimulating Hormone (FSH) and oestrogen levels at screening or from a historical sample), OR * Surgically sterile, OR * If they are of childbearing potential, must agree to practice two effective methods of contraception concurrently from the time of signing the informed consent form until 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception Male patients must: * Even if surgically sterilized (post-vasectomy with documentation of azoospermia), agree to practice effective barrier contraception during the entire study treatment period and through to 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception 7. Clinical laboratory values: 1. Absolute neutrophil count (ANC) ≥ 1 x 109/L 2. Platelet count ≥ 100 x 109/L 3. Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN) 4. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 × ULN. 5. Calculated creatinine clearance ≥ 30 mL/min
Exclusion criteria
* Participants meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Adverse events (AE) will be compared between active and placebo arm | Baseline to 24 months | 1. Proportion of AEs in the Ixazomib versus placebo arm in subjects with Relapsing Remitting Multiple Sclerosis (RRMS) 2. Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with RRMS 3. Proportion of AEs in the Ixazomib versus placebo arm in subjects with progressive MS 4. Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in subjects with progressive MS 5. Proportion of AEs in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS) 6. Proportion of serious AEs (SAEs) in the Ixazomib versus placebo arm in all subjects (subjects with RRMS and subjects with progressive MS) |
| Efficacy - the proportion of OCB IgG negative subjects will be compared between active and placebo arm | Baseline to 24 months | 1. Proportion of all subjects (Relapsing Remitting Multiple Sclerosis and progressive Multiple Sclerosis subjects) negative for Oligoclonal Bands Immunoglobulin G (OCB IgG) antibodies measured in Cerebrospinal Fluid (CSF) in the Ixazomib versus placebo arm at 24 months 2. Proportion of subjects negative for Oligoclonal Bands Immunoglobulin G (OCB IgG) antibodies measured in Cerebrospinal Fluid (CSF) in the Ixazomib versus placebo arm at 24 months in subjects with Relapsing Remitting Multiple Sclerosis (RRMS) 3. Proportion of subjects negative for Oligoclonal Bands Immunoglobulin G (OCB IgG) antibodies measured in Cerebrospinal Fluid (CSF) in the Ixazomib versus placebo arm at 24 months in subjects with progressive Multiple Sclerosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Magnetic Resonance Imaging (MRI) | Baseline to 24 months | Change in T2 lesion load and gadolinium enhancing lesions on brain MRI with Ixazomib versus placebo arm at 24 months |
| Change In Expanded Disability Status Scale (EDSS) with Ixazomib versus placebo arm at 24 months. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist | Baseline to 24 months | Change in EDSS with ixazomib versus placebo at 24 months. |
Countries
United Kingdom
Outcome results
None listed